The present invention, in general, relates to conversion of the carboxylic acid moiety of various compounds into amide derivatives of the compounds. More specifically, the present invention relates to secondary amide derivatives of non-steroidal antiinflammatory drugs (NSAIDs), particularly of indomethacin (an NSAID), that exhibit inhibition of cyclooxygenase-2 (COX-2) far exceeding inhibition of cyclooxygenase-1 (COX-1), and also, that still exhibit the analgesic, antiinflammatory, and/or antipyretic effect of the compound, i.e., of the NSAID, and moreover, also exhibit cancer inhibition, i.e., an antiangiogenic and/or antitumorigenic effect, in warm blooded vertebrate animals, including humans.
As discussed in more detail below, the COX enzyme is really two enzymes, COX-1 and COX-2, which serve different physiological and pathophysiological functions. As is well known, at antiinflammatory and/or analgesic doses, indomethacin, aspirin, and other NSAIDs effect great inhibition of COX-1, which protects the lining of the stomach from acid, along with relatively minimal inhibition of COX-2, which provokes inflammation in response to joint injury or a disease like arthritis. Also, certain NSAIDs possess essentially the same inhibitory activity against both COX-1 and COX-2. Thus, zeroing in on inhibition of COX-2 alone has been the goal of drug developers for several years in order to reduce or eliminate the GI. irritation caused by COX-1 inhibition.
More specifically, as discussed in Smith, Garavito, and DeWitt, xe2x80x9cD. L. Prostaglandin Endoperoxide H Synthases (Cyclooxygenases) -1 and -2xe2x80x9d, J. Biol. Chem., (1996) Vol. 271, pp. 33157-33160, the pertinent step in prostaglandin and thromboxane biosynthesis involves the conversion of arachidonic acid to PGH2, which is catalyzed by the sequential action of the COX and PER activities of PGHS, as set out in the following reaction scheme: 
That COX activity originates from two distinct and independently regulated enzymes, termed COX-1 and COX-2, is described in DeWitt and Smith, xe2x80x9cPrimary Structure of Prostaglandin G/H Synthase from Sheep Vesicular Gland Determined from the Complementary DNA Sequencexe2x80x9d, Proc. Natl. Acad. Sci. U.S.A. (1988) Vol. 85, pp. 1412-1416; Yokoyama and Tanabe, xe2x80x9cCloning of Human Gene Encoding Prostaglandin Endoperoxide Synthase and Primary Structure of the Enzymexe2x80x9d, Biochem. Biophys. Res. Commun. (1989) Vol. 165, pp. 888-894; and HIa and Neilson, xe2x80x9cHuman Cyclooxygenase-2-cDNAxe2x80x9d, Proc. Natl. Acad. Sci. U.S.A. (1992) Vol. 89, pp. 7384-7388.
COX-1 is the constitutive isoform and is mainly responsible for the synthesis of cytoprotective prostaglandins in the GI tract and for the synthesis of thromboxane, which triggers platelet aggregation in blood platelets. See, Allison, Howatson, Torrence, Lee, and Russell, xe2x80x9cGastrointestinal Damage Associated with the Use of Nonsteroidal Antiinflammatory Drugsxe2x80x9d, N. Engl. J. Med. (1992) Vol. 327, pp. 749-754.
On the other hand, COX-2 is inducible and short-lived. Its expression is stimulated in response to endotoxins, cytokines, and mitogens. See, Kujubu, Fletcher, Varnum, Lim, and Herschman, xe2x80x9cTIS10, A Phorbol Ester Tumor Promoter Inducible mRNA from Swiss 3T3 Cells, Encodes a Novel Prostaglandin Synthase/Cyclooxygenase Homologuexe2x80x9d, J. Biol. Chem. (1991) Vol. 266, pp. 12866-12872; Lee, Soyoola, Chanmugam, Hart, Sun, Zhong, Liou, Simmons, and Hwang, xe2x80x9cSelective Expression of Mitogen-Inducible Cyclooxygenase in Macrophages Stimulated with Lipopolysaccharidexe2x80x9d, J. Biol Chem. (1992) Vol. 267, pp. 25934-25938; and O""Sullivan, Huggins, Jr., and Mccall, xe2x80x9cLipopolysaccharide-Induced Expression of Prostaglandin H Synthase-2 in Aveolar Macrophages is Inhibited by Dexamethasone by not by Aspirinxe2x80x9d, Biochem. Biophys. Res. Commun. (1993) Vol.191, pp.1294-1300.
Importantly, COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells (monocytes/macrophages) and in the central nervous system. See, Masferrer, Zweifel, Manning, Hauser, Leahy, Smith, Isakson, and Seibert, xe2x80x9cSelective Inhibition of Inducible Cyclooxygenase-2 in vivo is Antiinflammatory and Nonulcerogenicxe2x80x9d, Proc. Natl. Acad. Sci. U.S.A. (1994) Vol. 91, pp. 3228-3232; Vane, Mitchell, Appleton, Tomlinson, Bishop-Bailey, Croxtall, and Willoughby, xe2x80x9cInducible Isoforms of Cyclooxygenase and Nitric Oxide Synthase in Inflammationxe2x80x9d, Proc. Natl. Acad. Sci. U.S.A. (1994) Vol.91, pp. 2046-2050; Harada, Hatanaka, Saito, Majima, Ogino, Kawamura, Ohno, Yang, Katori, and Yamamoto, xe2x80x9cDetection of Inducible Prostaglandin H Synthase-2 in Cells in the Exudate of Rat Carrageenin-Induced Pleurisyxe2x80x9d, Biomed. Res. (1994) Vol. 15, pp. 127-130; Katori, Harada, Hatanaka, Kawamura, Ohno, Aizawa, and Yamamoto, xe2x80x9cInduction of Prostaglandin H Synthase-2 in Rat Carrageenin-Induced Pleurisy and Effect of a Selective COX-2 Inhibitorxe2x80x9d, Advances in Prostaglandin, Thromboxane, and Leukotriene Research (1995) Vol. 23, pp. 345-347; and Kennedy, Chan, Culp, and Cromlish, xe2x80x9cCloning and Expression of Rat Prostaglandin Endoperoxide Synthase (Cyclooxygenase-2) cDNAxe2x80x9d, Biochem. Biophys. Res. Commun. (1994) Vol. 197, pp. 494-500.
Hence, the differential tissue distribution of COX-1 and COX-2 provides a basis for the development of drugs that are selective COX-2 inhibitors (i.e., specificity for inhibition of COX-2 far exceeds inhibition of COX-1) as antiinflammatory, analgesic, and/or antipyretic agents with minimization of or without the GI and hematologic liabilities from COX-1 inhibition that plague most all currently marketed NSAIDs, most of which inhibit both COX-1 and COX-2, with specificity for COX-1 inhibition greatly exceeding that for COX-2 inhibition, although some have essentially similar inhibitory activity against both COX-1 and COX-2. See, for instance, Meade, Smith, and DeWift, xe2x80x9cDifferential Inhibition of Prostaglandin Indoperoxide Synthase (Cyclooxygenase) Isozymes by Aspirin and Other Non-Steroidal Antiinflammatory Drugsxe2x80x9d, J. Biol. Chem., (1993) Vol. 268, pp. 6610-6614.
Detailed SAR studies have been reported for two general structural classes of selective COX-2 inhibitors (specificity for COX-2 inhibition far exceeds COX-1 inhibition) including certain acidic sulfonamides and diarylheterocyclics. The in vivo activities of these selective COX-2 inhibitors validate the concept that selective COX-2 inhibition is antiinflammatory and nonulcerogenic, as discussed in the following journal articles. Gans, Galbraith, Roman, Haber, Kerr, Schmidt, Smith, Hewes, and Ackerman, xe2x80x9cAnti-Inflammatory and Safety Profile of DuP 697, a Novel Orally Effective Prostaglandin Synthesis Inhibitorxe2x80x9d, J. Pharmacol Exp. Ther. (1990) Vol. 254, pp. 180-187; Penning, Talley, Bertenshaw, Carter, Collins, Docter, Graneto, Lee, Malecha, Miyashiro, Rogers, Rogier, Yu, Anderson, Burton, Cogburn, Gregory, Koboldt, Perkins, Seibert, Veenhuizen, Zhang, and Isakson, xe2x80x9cSynthesis and Biological Evaluation of the 1,5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors: Identification of 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib)xe2x80x9d, J. Med. Chem. (1997) Vol. 40, pp. 1347-1365; Khanna, Weier, Yu, Xu, Koszyk, Collins, Koboldt, Veenhuizen, Perkins, Casler, Masferrer, Zhang, Gregory, Seibert, and Isakson, xe2x80x9c1,2-Diarylimidazoles as Potent Cyclooxygenase-2 Selective, and Orally Active Antiinflammatory Agentsxe2x80x9d, J. Med. Chem. (1997) Vol. 40, pp. 1634-1647; Khanna, Weier, Yu, Collins, Miyashiro, Koboldt, Veenhuizen, Curie, Siebert, and Isakson, xe2x80x9c1,2-Diarylpyrroles as Potent and Selective Inhibitors of Cyclooxygenase-2xe2x80x9d, J. Med. Chem. (1997) Vol. 40, pp. 1619-1633; Tsuji, Nakamura, Konishi, Tojo, Ochi, Senoh, and Matsuo, xe2x80x9cSynthesis and Pharmacological Properties of 1,5-Diarylyrazoles and Related Derivativesxe2x80x9d, Chem. Pharm. Bull. (1997) Vol. 45, pp. 987-995; Riendeau, Percival, Boyce, Brideau, Charleson, Cromlish, Ethier, Evans, Falgueyret, Ford-Hutchinson, Gordon, Greig, Gresser, Guay, Kargman, Leger, Mancini, O""Neill, Quellet, Rodger, Therien, Wang, Webb, Wong, Xu, Young, Zamboni, Prasit, and Chan, xe2x80x9cBiochemical and Pharmacological Profile of a Tetrasubstituted Furanone as a Highly Selective COX-2 Inhibitorxe2x80x9d, Br. J. Pharmacol. (1997) Vol. 121, pp. 105-117; Roy, Leblanc, Ball, Brideau, Chan, Chauret, Cromlish, Ethier, Gauthier, Gordon, Greig, Guay, Kargman, Lau, O""Neill, Silva, Therien, Van Staden, Wong, Xu, and Prasit, xe2x80x9cA New Series of Selective COX-2 Inhibitors: 5,6-Diarylthiazolo[3,2-b][1,2,4]-triazolesxe2x80x9d, Bioorg. Med. Chem. Lett. (1997) Vol. 7, pp. 57-62; Thxc3xa9rien, Brideau, Chan, Cromlish, Gauthier, Gordon, Greig, Kargman, Lau, Leblanc, Li, O""Neill, Riendeau, Roy, Wang, Xu, and Prasit, xe2x80x9cSynthesis and Biological Evaluation of 5,6-Diarylimidazo[2.1-b]thiazoles as Selective COX-2 Inhibitorsxe2x80x9d, Bioorg. Med. Chem. Lett. (1997) Vol. 7, pp. 47-52; Li, Norton, Reinhard, Anderson, Gregory, Isakson, Koboldt, Masferrer, Perkins, Seibert, Zhang, Zweifel, and Reitz, xe2x80x9cNovel Terphenyls as Selective Cyclooxygenase-2 Inhibitors and Orally Active Anti-Inflammatory Agentsxe2x80x9d, J. Med. Chem. (1996) Vol. 39, pp. 1846-1856; Li, Anderson, Burton, Cogburn, Collins, Garland, Gregory, Huang, Isakson, Koboldt, Logusch, Norton, Perkins, Reinhard, Seibert, Veenhuizen, Zhang, and Reitz, xe2x80x9c1 ,2-Diarylcyclopentenes as Selective Cyclooxygenase-2 Inhibitors and Orally Active Anti-Inflammatory Agentsxe2x80x9d, J. Med. Chem. (1995) Vol. 38, pp. 4570-4578; Reitz, Li, Norton, Reinhard, Huang, Penick, Collins, and Garland, xe2x80x9cNovel 1,2-Diarylcyclopentenes are Selective Potent and Orally Active Cyclooxygenase Inhibitorsxe2x80x9d, Med. Chem Res. (1995) Vol. 5, pp. 351-363; Futaki, Yoshikawa, Hamasaka, Arai, Higuchi, lizuka, and Otomo, xe2x80x9cNS-398, A Novel Nonsteroidal Antiinflammatory Drug with Potent Analgesic and Antipyretic Effects, which Causes Minimal Stomach Lesionsxe2x80x9d, Gen. Phamacol. (1993) Vol.24, pp. 105-110; Wiesenberg-Boetcher, Schweizer, Green, Muller, Maerki, and Pfeilschifter, xe2x80x9cThe Pharmacological Profile of CGP 28238, A Novel Highly Potent Anti-Inflammatory Compoundxe2x80x9d, Drugs Exptl Clin Res. (1989) Vol. XV, pp. 501-509; Futaki, Takahashi, Yokoyama, Arai, Higuchi, and Otomo, xe2x80x9cNS-398, A New Anti-Inflammatory Agent, Selectively Inhibits Prostaglandin G/H Synthase/Cyclooxygenase (COX-2) Activity in vitroxe2x80x9d, Prostaglandins (1994) Vol.47, pp. 55-59; Klein, Nusing, PfeiIschifter, and Ullrich, xe2x80x9cSelective Inhibition of Cyclooxygenase-2xe2x80x9d, Biochem. Pharmacol. (1994) Vol. 48, pp.1605-1610; Li, Black, Chan, Ford-Hutchinson, Gauthier, Gordon, Guay, Kargman, Lau, Mancini, Quimet, Roy, Vickers, Wong, Young, Zamboni, and Prasit, xe2x80x9cCyclooxygenase-2 Inhibitors. Synthesis and Pharmacological Activities of 5-Methanesulfonamido-1-indanone Derivativesxe2x80x9d, J. Med. Chem. (1995) Vol. 38, pp.4897-8905; Prasit, Black, Chan, Ford-Hutchinson, Gauthier, Gordon, Guay, Kargman, Lau, Li, Mancini, Quimet, Roy, Tagari, Vickers, Wong, Young, and Zamboni, xe2x80x9cL-745,337: A Selective Cyclooxygenase-2 Inhibitorxe2x80x9d, Med. Chem. Res. (1995) Vol. 5, pp. 364-374; Tanaka, Shimotori, Makino, Aikawa, Inaba, Yoshida, and Takano, xe2x80x9cPharmacological Studies of the New Antiinflammatory Agent 3-Formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. 1st Communication: Antiinflammatory, Analgesic and Other Related Propertiesxe2x80x9d, Arzniem.-Forsch./Drug Res. (1992) Vol. 42, pp. 935-944; Nakamura, Tsuji, Konishi, Okumura, and Matsuo, xe2x80x9cStudies on Anti-Inflammatory Agents. I. Synthesis and Pharmacological Properties of 2xe2x80x2-(phenylthio)methanesulfonamides and Related Derivativesxe2x80x9d, Chem. Pharm. Bull. (1993) Vol. 41, pp. 894-906; Chan, Boyce, Brideau, Ford-Hutchinson, Gordon, Guay, Hill, Li, Mancini, Penneton, Prasit, Rasori, Riendeau, Roy, Tagari, Vickers, Wong, and Rodger, xe2x80x9cPharmacology of a Selective Cyclooxygenase-2 Inhibitor, L-745,337: A Novel Nonsteroidal Anti-Inflammatory Agent with an Ulcerogenic Sparing Effect in Rat and Nonhuman Primate Stomachxe2x80x9d, J. Pharmacol. Exp. Ther. (1995) Vol. 274, pp. 1531-1537; and Graedon and Graedon, xe2x80x9cPills Promise Relief without Ulcersxe2x80x9d, The Raleigh, North Carolina News and Observer, p. 8D (Sep. 13, 1998) which addresses, in general terms, the development of celecoxib, meloxicam, and vioxx as selective COX-2 inhibitors.
Representative acidic sulfonamides and diarylheterocyclics that have been reported as selective COX-2 inhibitors in the journal articles mentioned in the above paragraph are: 
Although acidic sulfonamides and diarylheterocyclics have been extensively studied as selective COX-2 inhibitors, there are very few reports on converting NSAIDs that are selective CQX-1 inhibitors into selective COX-2 inhibitors. See, Black, Bayly, Belley, Chan, Charleson, Denis, Gauthier, Gordon, Guay, Kargman, Lau, Leblanc, Mancini, Quellet, Percival, Roy, Skorey, Tagari, Vickers, Wong, Xu, and Prasit, xe2x80x9c. From Indomethacin to a Selective COX-2 Inhibitor: Development of Indolalkanoic Acids as Potent and Selective Cyclooxygenase-2 Inhibitorsxe2x80x9d, Bioorg. Med. Chem. Lett. (1996) Vol. 6, pp. 725-730; Luong, Miller, Barnett, Chow, Ramesha, and Browner, xe2x80x9cFlexibility of the NSAID Binding Site in the Structure of Human Cyclooxygenase-2xe2x80x9d, Nature Structural Biol. (1996) Vol. 3, pp. 927-933; and Kalgutkar, Crews, Rowlinson, Garner, Seibert, and Marnett, xe2x80x9cAspirin-Like Molecules that Covalently Inactivate Cyclooxygenase-2xe2x80x9d, Science (1998) Vol. 280, pp.1268-1270.
Also, interesting is U.S. Pat. No. 5,681,964 (issued in 1997) to Ashton et al., assignors to the University of Kentucky Research Foundation, which shows conversion of indomethacin (an NSAID) into certain ester derivatives with concomitant reduction of GI irritation (see, FIG. 1 of U.S. Pat. No. 5,681,964 for the structure of the ester derivatives). Additionally, U.S. Pat. Nos. 5,607,966 (Parent) (issued in 1997) and 5,811,438 (CIP) (issued in 1998), both to Hellberg et al., assignors to Alcon Laboratories, show conversion of various NSAIDs (such as indomethacin) into certain ester derivatives and amide derivatives (which are useful as antioxidants and inhibitors of 5-lipoxygenase) but do not address COX-2 selective inhibition.
Moreover, although U.S. Pat. Nos. 3,285,908 (issued in 1966) and 3,336,194 (issued in 1967), both to Shen, assignor to Merck and Co., Inc., describe various secondary and tertiary amide derivatives of indomethacin, the patents fail to address COX inhibition, probably because COX inhibition (both COX-1 and COX-2) was undiscovered in the 1960""s, and thus fail to recognize that tertiary amide derivatives do not inhibit either COX-1 or COX-2. (Also, see comparison compounds 9 and 10 in the Examples below.) However, U.S. Pat. Nos. 5,436,265 (issued in 1995) to Black et al. and 5,510,368 (issued in 1996) to Lau et al., both patents assigned to Merck Frosst Canada, Inc., describe, respectively, 1-aroyl-3-indolyl alkanoic acids and N-benzyl-3-indoleacetic acids as COX-2 selective inhibitors.
In the present investigation, the possibility has been explored for designing selective COX-2 inhibitors using as templates various compounds, such as NSAIDs, (1) that are selective COX-1 inhibitors or (2) that have essentially the same inhibitory activity for both COX-1 and COX-2. These two kinds of compounds are collectively referred to as compounds that are not selective COX-2 inhibitors.
More particularly, analysis of the human COX-2 crystal structure complexed with zomepirac-derived selective COX-2 inhibitors indicates that the structural basis for selectivity by zomepirac-derived compounds is different from that of diarylheterocyclics. See, Luong et al. mentioned above. Unlike diaryiheterocyclics, zomepirac analogs do not utilize the side pocket; instead they breech the constriction at the mouth of the COX active site occupied by Arg106 and Tyr341 and project down the lobby region. The projection into this sterically uncongested region in the COX-2 active site opens the possibility that making a wide range of analogs of COOH-containing NSAIDs, each with a different pendent functional group replacing the OH of the COOH, would accomplish many purposes related to drug discovery or development. For example, certain pendent groups could improve water-solubility, bioavailability, or pharmacokinetics. Another possibility would be to attach a pendent pharmacophore in order to target a completely different protein leading to compounds with dual pharmacological functions.
Abbott Laboratories and Parke-Davis have attempted the pharmacophore approach. See, respectively, Kolasa, Brooks, Rodriques, Summers, Dellaria, Hulkower, Bouska, Bell, and Carter, xe2x80x9cNonsteroidal Anti-Inflammatory Drugs as Scaffolds for the Design of 5-Lipoxygenase Inhibitorsxe2x80x9d, J. Med. Chem. (1997) Vol. 40, pp. 819-824; and Flynn, Capiris, Cetenko, Connor, Dyer, Kostlan, Niese, Schrier, and Sircar, xe2x80x9cNonsteroidal Antiinflammatory Drug Hydroxamic Acids. Dual Inhibitors of Both Cyclooxygenase and 5-Lipoxygenasexe2x80x9d, J. Med. Chem. (1990) Vol. 33, pp. 2070-2072. Both Kolasa et al. and Flynn et al. reported that replacement of the carboxylic acid group in NSAIDs with a hydroxamic acid moiety or a hydroxyurea moiety provided dual inhibitors of COX and 5-lipoxygenase. Nevertheless, none of the analogs displayed any significant selective COX-2 inhibition, and furthermore the hydroxamates underwent facile hydrolysis.
However, nothing in the above-discussed literature suggests that converting a COOH-containing drug, such as-a COOH-containing NSAID, that is not selective for COX-2 inhibition into a derivative that is selective for COX-2 inhibition would also result in that derivative being a cancer inhibitor. Nevertheless, it is interesting to note that sulindac sulfide (an NSAID which contains a COOH moiety as well as a methyl sulfide moiety) is a 40-fold more potent inhibitor against COX-1 than COX-2, yet also exhibits inhibition of tumors. On the other hand, a derivative, namely sulindac sulfone (which contains a COOH moiety as well as a methyl sulfone moiety) does not inhibit either COX-1 or COX-2, but still exhibits inhibition of tumors.
Thus, it would be desirable to find certain COOH-containing drugs, such as COOH-containing NSAIDs, which are not selective COX-2 inhibitors (either display an inhibition for COX-1 far exceeding inhibition of COX-2 or display essentially the same inhibition for COX-1 and COX-2) that would, when converted into certain derivatives, become selective COX-2 inhibitors (display an inhibition for COX-2 far exceeding inhibition for COX-1), as well as retain the analgesic, antiinflammatory, and/or antipyretic effect of the drug, and yet exhibit other effects not exhibited by the drug prior to derivatization, such as cancer inhibition.
Surprisingly with the present invention, it has been found that derivatization of the carboxylic acid moiety of certain compounds, such as certain NSAIDs, that are not selective COX-2 inhibitors, such as indomethacin, into secondary amide analogs creates isozyme specificity for COX-2. Moreover, the resultant secondary amide derivative is not only a selective COX-2 inhibitor, but also is a cancer inhibitor, i.e., exhibits antiangiogenic and/or antitumorigenic activity, and preferably, also retains the analgesic, antiinflammatory, and/or antipyretic of the compound.
Therefore, the present invention provides a method for cancer treatment in a warm blooded vertebrate animal. The method comprises administering to the animal a treatment effective amount sufficient to inhibit cancer of a carboxylic acid secondary amide derivative of a compound. The derivative is selective for inhibition of cyclooxygenase-2. The compound (a) is a cyclooxygenase inhibitor but is not selective for inhibition of cyclooxygenase-2 and (b) contains a carboxylic acid moiety or a pharmaceutically acceptable salt thereof. Preferably, the compound is a non-steroidal antiinflammatory drug, or a pharmaceutically acceptable salt thereof.
Hence, it is an object of the invention to provide a cancer treatment that minimizes or obviates GI irritation.
Moreover, it is an advantage of the present invention that the cancer treatment is also analgesic, antiinflammatory, and/or antipyretic, absent the concomitant administration of an analgesic, antiinflammatory, and/or antipyretic drug, such as an NSAID or a pharmaceutically acceptable salt thereof.
Some of the objects of the invention having been stated above, other objects will become evident as the description proceeds, when taken in connection with the Laboratory Examples as described below.
The present invention involves a method for treating cancer in an animal that is a warm-blooded vertebrate. Therefore, the invention concerns mammals and birds.
Contemplated is the treatment of mammals such as humans, as well as those mammals of importance due to being endangered (such as Siberian tigers), of economical importance (animals raised on farms for consumption by humans) and/or social importance (animals kept as pets or in zoos) to humans, for instance, carnivores other than humans (such as cats and dogs), swine (pigs, hogs, and wild boars), ruminants (such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels), and horses. Also contemplated is the treatment of birds, including the treatment of those kinds of birds that are endangered, kept in zoos, as well as fowl, and more particularly domesticated fowl, i.e., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economical importance to humans.
Thus, contemplated is the treatment of livestock, including, but not limited to, domesticated swine (pigs and hogs), ruminants, horses, poultry, and the like.
More particularly, a treatment effective amount of a secondary amide derivative of a carboxylic acid-containing compound is administered to the warm-blooded vertebrate animal. Thus, the invention comprises administration of the secondary amide derivative in concentrations calculated to provide the animal being treated with the appropriate milieu to provide prevention, control, or cessation of cancer. Moreover, in the preferred embodiment, the secondary amide derivative possesses an analgesic, antiinflammatory, and/or antipyretic property as possessed by the carboxylic acid-containing compound prior to derivatization, and thus, the cancer treatment provides an analgesic, antiinflammatory, and/or antipyretic effect in the animal and is free of concomitant administration of another drug for providing such effect.
By carboxylic-acid containing compound or COOH-containing compound as used herein in connection with the present invention, it is intended to include pharmaceutically acceptable acid salts of the compound. Thus, for instance, the COOH moiety includes COOM, where M is Na and the like.
The derivatives useful in the method of the present invention are secondary amide derivatives of drugs having a carboxylic acid moiety or a pharmaceutically acceptable salt thereof, for instance, secondary amide derivatives of non-steroidal anti-inflammatory drugs having a carboxylic acid moiety or a pharmaceutically acceptable salt thereof. A number of chemical classes of non-steroidal anti-inflammatory drugs have been identified, as described in CRC Handbook of Eicosanoids: Prostaglandins, and Related Lipids, Volume II, Drugs Acting Via the Eicosanoids, pages 59-133, CRC Press, Boca Raton, Fla. (1989).
The NSAID may be selected, therefore, from a variety of chemical classes including, but not limited to, fenamic acids, such as flufenamic acid, niflumic acid, and mefenamic acid; indoles, such as indomethacin, sulindac, and tolmetin; phenylalkanoic acids, such as suprofen, ketorolac, flurbiprofen, and ibuprofen; and phenylacetic acids, such as diclofenac. Further examples of NSAIDs are listed below:
More specifically, preferred secondary amide derivatives useful in the present invention include, but are not limited to, secondary amide derivatives of the following COOH-containing NSAIDs: 6-methoxy-a-methyl-2-naphthylacetic acid (and its Na acid salt form known as naproxen), meclofenamic acid, and diclofenac, with secondary amide derivatives of indomethacin being preferred, and that indomethacin derivative described below as compound 11 being especially preferred. Also, the secondary amide derivatives of indomethacin, where the Cl at the 4-position of the benzoyl moiety is replaced with Br or F, should work in the present invention.
Even more preferred are the secondary amide derivatives of indomethacin including, but are not limited to, indomethacin-N-methyl amide, indomethacin-N-ethan-2-of amide, indomethacin-N-octyl amide, indomethacin-N-nonyl amide, indomethacin-N-(2-methylbenzyl) amide, indomethacin-N-(4-methylbenzyl) amide, indomethacin-N-((R)-,4-dimethylbenzyl) amide, indomethacin-N-((S)-,4-dimethylbenzyl) amide, indomethacin-N-(2-phenethyl) amide, indomethacin-N-(4-fluorophenyl) amide, indomethacin-N-(4-chlorophenyl) amide, indomethacin-N-(4-acetamidophenyl) amide, indomethacin-N-(4-methylmercapto)phenyl amide, indomethacin-N-(3-methylmercaptophenyl) amide, indomethacin-N-(4-methoxyphenyl) amide, indomethacin-N-(3-ethoxyphenyl) amide, indomethacin-N-(3,4,5-trimethoxyphenyl) amide, indomethacin-N-(3-pyridyl) amide, indomethacin-N-5-((2-chloro)pyridyl) amide, indomethacin-N-5-((1-ethyl)pyrazolo) amide, indomethacin-N-(3-chloropropyl) amide, indomethacin-N-methoxycarbonylmethyl amide, indomethacin-N-2-(2-L-methoxycarbonylethyl) amide, indomethacin-N-2-(2-D-methoxycarbonylethyl) amide, indomethacin-N-(4-methoxycarbonylbenzyl) amide, indomethacin-N-(4-methoxycarbonylmethylphenyl) amide, indomethacin-N-(2-pyrazinyl) amide, indomethacin-N-2-(4-methylthiazolyl) amide, indomethacin-N-(4-biphenyl) amide, and combinations thereof.
The secondary amide derivative may be administered to the animal as a suppository or as a supplement to fluids that are administered internally or parenterally, for instance nutriment fluids such as intervenous sucrose solutions. Furthermore, intraoral (such as buccal or sublingual) administration or transdermal (such as with a skin patch) administration to the animal is also contemplated. A good discussion of intraoral administration can be seen in U.S. Pat. No. 4,229,447 issued Oct. 21, 1980 to Porter and U.S. Pat. No. 5,504,086 issued Apr. 2, 1996 to Ellinwood and Gupta. A good discussion of transdermal administration can be seen in U.S. Pat. No. 5,016,652 issued May 21, 1991 to Rose and Jarvik.
Additionally, administration to the animal may be by various oral methods, for instance as a tablet, capsule, or powder (crystalline form) that is swallowed. Also, oral administration may include that the secondary amide derivative is admixed in a carrier fluid appropriate therefor so that it is administered as a liquid (solution or suspension) that is drunk. When the secondary amide derivative is admixed in a carrier fluid, appropriate fluids include, but are not limited to, water, rehydration solutions (i.e., water with electrolytes such as potassium citrate and sodium chloride, for instance the solution available under the trade name RESOL(copyright) from Wyeth Laboratories), nutritional fluids (i.e., milk, fruit juice), and combinations thereof. Thus, the oral administration may be as a component of the diet, such as human food, animal feed, and combinations thereof.
In addition to oral administration such as by way of the mouth, contemplated also is administration of a solution or suspension to the esophagus, stomach, and/or duodenum, such as by gavage, i.e., by way of a feeding tube. Gavage type of administration is useful forwhen the cancer has progressed and the animal can no longer swallow food, medicine, et cetera, by mouth.
Hence, it is also contemplated that additional ingredients, such as various excipients, carriers, surfactants, nutriments, and the like, as well as various medicaments other than a secondary amide derivative, orcombinations thereof, may be present together with the secondary amide derivative, whatever the form that the derivative is in. Medicaments other than a secondary amide derivative may include, but are not limited to, osmolytic polyols and osmolytic amino acids (i.e., myo-inositol, sorbitol, glycine, alanine, glutamine, glutamate, aspartate, proline, and taurine), cardiotonics (i.e., glycocyamine), analgesics, antibiotics, electrolytes (i.e., organic or mineral electrolytes such as salts), and combinations thereof.
A suitable dosing amount of secondary amide derivative for administration to the animal should range from about 0.5 mg to about 7.0 mg per kg of body weight of the animal per day, more preferably from about 1.5 mg to about 6.0 mg per kg of body weight of the animal per day, and even more preferably from about 2.0 mg to about 5.0 mg per kg of body weight of the animal per day. Administration may be one or more times per day to achieve the total desired daily dose. Of course, the amount can vary depending on the severity of the cancer and/or the age of the animal.
The present invention should be useful in the treatment of cancer in animals, wherein the cancer is caused by pathogens (i.e., parasites, bacteria, protozoa, and viruses, including toxic agents in food), nutritional factors (i.e., excess mineral salts, excess protein, allergic agents in food, undigestible food components, or poor quality ingredients in food), environmental factors that act as stressors or pollutants (i.e., heat, chilling, shipment of animals, or toxins such as from air and/orwater pollution), and/or physiological disorders such as those of the digestive tract, pulmonary/circulatory system, liver, kidneys, colon, and/or pancreas.